Abstract There are very few systematic studies on humans that focus on changing the underlying traumatic memory once PTSD has been established. The proposed project is a translational study based on our work with animal models of PTSD in which coricosterone augmented extinction of contextual fear memories. The study design is a double-blind randomized controlled clinical trial involving eighty-eight OEF/OIF veterans with combat-related PTSD. We plan to pair multiple fear memory reactivations, using a scripted imagery technique, with an oral glucocorticoid or placebo. Participants will be followed at 1, 3, and 6 months post intervention to measure the longevity of the expected effect. Outcome measures will include PTSD symptom severity, depression symptoms severity, and physiological measures. Specific Aims/Hypothesis: Aim 1: Examine the effects of glucocorticoid administration following traumatic memory reactivation on psychiatric symptoms in veterans with combat-related PTSD. Specific hypotheses to be tested: (A) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate fewer PTSD and depression symptoms one week later, compared to those who receive a placebo after traumatic memory reactivation. (B) The glucocorticoid reduction effects will be cumulative;that is, reduction will persist, and further post- reactivation glucocorticoid administration will further reduce symptoms. (C) Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for subjects receiving an exogenous glucocorticoid compared to those subjects receiving placebo. Aim 2: Examine the effects of glucocorticoid administration following traumatic memory reactivation on physiological responses to veteran's personal combat memories. (D) Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation will demonstrate decreased physiological responses one week later, compared to those who receive a placebo after traumatic memory reactivation. (E) As with the psychological measures, suppression of the physiological measures will demonstrate both persistence over time and accumulation with subsequent post-reactivation glucocorticoid administration. PUBLIC HEALTH RELEVANCE: Project Narrative Prevalence rates of combat-related post-traumatic stress disorder (PTSD) are increasing because of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments, with the estimated risk for PTSD from OEF/OIF service ranging from 11% to 18%. PTSD is characterized by intrusive memories in the form of unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic event. These memories are associated with intense distress and involve excessive physiological and psychological responses to trauma related stimuli. Current research efforts are focused on exploring the underlying neurochemical changes associated with PTSD in an effort to prevent or treat associated traumatic memories. To date, there have been very few systematic studies on humans that focus on changing the underlying traumatic memories once PTSD has been established. Memory can be changed in various ways including interference with reconsolidation of an established fear memory or by extinction, in which new memories associated with the trauma are formed. A traditional behavior therapy called exposure therapy uses the same process of extinction that we are using in the proposed study. Although effective, this therapy is not widely used because of barriers perceived by the providers of therapy as well as the recipients. The proposed study is a novel approach to treatment for established PTSD, applying an animal model of fear memory extinction to humans, to augment the extinction of underlying traumatic memories related to combat by pairing reactivation of a traumatic memory with a glucocorticoid. We will measure veterans'responses to scripts of their own combat traumas by looking at their physiological responses as well as self-reported psychiatric symptoms of PTSD and depression as well as clinician rated assessments of PTSD. The results of this study may offer a unique, inexpensive, and rapid method to treat PTSD, as well as lay the groundwork for the development of other pharmacotherapeutic agents that specifically target the extinction of combat-related fear memories. Although we are not developing a new type of exposure therapy, because we are using the same extinction principles as traditional exposure therapy uses, the information provided by this study will lay the groundwork for future studies combining pharmacotherapy and behavior therapy. The information gained from this study will be applicable not only to veterans who have combat-related PTSD, but to any individual with suffering intrusive memories from any type of trauma.